Effector T cell plasticity: flexibility in the face of changing circumstances - PubMed (original) (raw)
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Effector T cell plasticity: flexibility in the face of changing circumstances
Kenneth M Murphy et al. Nat Immunol. 2010 Aug.
Abstract
As more states of CD4 T cell differentiation are uncovered, their flexibility is also beginning to be recognized. Components that control the plasticity of CD4 T cell populations include cellular conditions, clonality, transcriptional circuitry and chromatin modifications. Appearance of cellular flexibility may arise from truly flexible genetic programs or, alternatively, from heterogeneous populations. New tools will be needed to define the rules that allow or prohibit cellular transitions.
Figures
Figure 1
Re-enforcement and destabilization of CD4+ T cell subsets. These four CD4+ subsets are induced in distinct conditions, but also can be reinforced or destabilized by other conditions, as discussed throughout the text.
Figure 2
Transitions of CD4+ T cell subsets. Naïve T cells, when triggered, behave as an ‘unstable state’ that can transition into various other subsets, depending on the conditions as indicated. The diagram suggests a possible hierarchy of stability. Experimentally observed transitions are indicated, along with the required conditions and factors that appear to mediate each step. On the left, subsets that maintain IL-12 receptor remain responsive to IL-12, while on the right, TH2 cells loose IL-12R expression. A hybrid state of TH1+2 has been observed to be induced from TH2 cells, in response to type I interferons, and IFN-γ and IL-12. Known interactions between transcription factors are indicated. Subsets whose status is still uncertain are not presented.
Figure 3
Transcriptional circuits can stabilize or destabilize CD4+ T cell subsets. The relative stability of states is shown by a hypothetical energy function, with more stable states residing within low energy ‘wells’. The mutual antagonism between T-bet and GATA-3 activity makes the states that co-express the two factors unstable. The positive feedback loops known to reinforce the expression of these factors stabilize the states with high expression of one of the two factors.
Figure 4
Possible transcription factor interactions regulating intermediate CD4+ T cell transitions. (a) Hypothetical circuit in which Foxp3 inhibits the activity of RORγt, without a reciprocal inhibition or feedback from RORγt. This circuit might favor iTreg development over TH17 development, making iTreg more stable. Without continuous stimulus by IL-6 to induce RORγt, Foxp3 might tend to repress TH17 development. (b) This hypothetical TH17 state is stabilized despite inhibition of RORγt by Foxp3 due to a known feedback loop, in which RORγt induces expression of IL-21, which acts in an autocrine manner to further induce STAT3 and stimulate RORγt expression. This feedback stabilizes the TH17 state relative to iTreg cells. (c) The transcriptional inhibitor Bcl-6 inhibits its own transcription. Such a mechanism could destabilize the TFH phenotype, consistent with the fact that in vitro cultures of TFH phenotype cells have not been reported as stable, in contrast to the robust stability of TH1 and TH2 cells.
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